This Program Project Grant renewal application describes studies we plan to perform as a continuation of our previous project on the role of vascular endothelial cells in the regulation of cardiovascular function in a variety of physiological and pathophysiological states. The project leaders represent related research disciplines, each of which will contribute to the collaborative efforts of the investigators. The common theme of the projects is the multifaceted role of and the interaction among the locally released, endothelium-derived mediators - i.e., nitric oxide, oxygen free radical species and prostaglandins - in the regulation of vascular smooth muscle functions, vascular tone and parenchymal cell metabolism in heart and skeletal muscle of rats, dogs and humans. The participating investigators have been in the forefront of research in this area and it is anticipated that, as a result of the coordinated program proposed, the role of endothelial mediators in blood vessel biology as well as their possible role in the changes evoked by exercise training, and disease states, such as heart failure, will become clearer. PROJECT 1 will study the production of reactive oxygen species and the consequences of oxidant-nitric oxide interactions in normal coronary vessels and vessels obtained from models of heart failure and exercise training. PROJECT 2 will examine the pathophysiologic relevance of the disappearance of nitric oxide from the circulation of the failing heart and the consequences of this on coronary vascular regulation and oxygen metabolism of cardiac myocytes. PROJECT 3 will investigate the effects of the loss of endothelial nitric oxide formation in the failing heart on necrotic and apoptotic myocyte cell death and on the metabolism of reactive oxygen species leading to ventricular dysfunction. PROJECT 4 will have as its goal the study of the mechanisms of shear stress dependent dilation of arterioles and the contribution of endothelial mediators to the altered regulation of microvascular function after exercise training and heart failure. An Administrative Core will support the research projects. This multidisciplinary approach to the study of the contribution of endothelial cells to vascular and parenchymal function holds the potential of leading to a better understanding of circulatory physiology as well as the pathogenesis and, possibly, therapy of a variety of disease states.